The influential comedian was known for his neurotic observational humor, particularly about romantic relationships, and his no-holds-barred skewering of showbiz in his inventive TV shows. “The Larry Sanders Show” was one of the early pillars of HBO’s original series strategy, garnering Emmy Awards and critical acclaim during its 1992-1998 run.

Born in Chicago, he was raised in Tucson, Ariz., and started out majoring in electrical engineering before completing a marketing degree at the University of Arizona. After moving to Los Angeles, he sold a script for “Sanford and Son” and also wrote for “Welcome Back, Kotter.” He guest-hosted on “The Tonight Show Starring Johnny Carson” and was in consideration to become Carson’s replacement.

In 1986, he created his own sitcom “It’s Garry Shandling’s Show,” also an early original series effort for Showtime. The show, also co-created by Alan Zweibel, was nominated for four Emmys, and ran until 1990. The show was noted for being one that often broke the fourth wall, with Shandling speaking directly to the audience, and he played a version of himself: a stand-up comedian aware of the fact that he is a sitcom character. Even the theme song was self-referential from the opening line: “This is the theme to Garry’s show…”

The seeds of “Larry Sanders Show” were planted on Showtime in 1986 when Shandling hosted “The Garry Shandling Show 25th Anniversary Special,” a parody of a Johnny Carson-esque anniversary special. He starred and co-created “Larry Sanders Show” for HBO, set in the office of a fictional late-night talk show, with Dennis Klein. Shandling was nominated for 18 Emmys for the show and, along with Peter Tolan, won an Emmy for the series finale.

“The Larry Sanders Show” was said to have a lasting impact on TV comedy, influencing such series as “Curb Your Enthusiasm.” It cracked several “best of” lists, including Time’s 100 Best TV Shows of All Time. Judd Apatow was among the staff writers on the show who went on to become a major player in the industry.

NBC offered him $5 million to take over “Late Night” when David Letterman moved to CBS in 1993, but he declined. He was also offered “The Late Late Show” but declined to do the “Larry Sanders Show.”

He was also a formidable host, hosting the Grammys in 1990, 1993 and 1994, and the Emmys in 2000 and 2004.

He appeared in and did voices for films including “Iron Man 2,” “Captain America: The Winter Soldier,” “Dr. Dolittle,” “Zoolander” and “Over the Hedge.”

Shandling was never married and did not have children. TMZ first reported the news.